We read with interest the article by Lee et al,1 who conducted a case-case-control study to evaluate risk factors for fungemia caused by fluconazole-resistant Candida glabrata. The authors identified previous fluconazole use (and linezolid use) as a significant risk factor for fluconazole-resistant C glabrata fungemia, whereas cefepime and metronidazole use were independent risk factors for fluconazole-susceptible C glabrata fungemia. Although with a smaller number of patients, a similar investigation with the same study design was previously carried out by our group.2 In accordance with Lee et al,1 our study had identified prior fluconazole exposure as the most important predisposing factor for subsequent C glabrata fungemia due to a less-susceptible isolate. We found that diabetes mellitus and central venous catheters were other independent risk factors for fungemia caused by a fluconazole–less-susceptible isolate, whereas previous surgery and central venous catheterization were independent risk factors for fungemia due to a susceptible isolate; unfortunately, these variables do not appear to have been analyzed by Lee et al.1 With regard to the antibiotic use, we did not find a significant association between fluconazole-resistant C glabrata fungemia and the use of any antibiotics; it was not possible to assess the impact of linezolid use because this drug was not largely used in Italy during the first years of our study. We found that cephalosporin (and glycopeptide or aminoglycoside) use was significantly associated with fluconazole-susceptible C glabrata fungemia, but in univariate analysis only. We agree with the authors' hypothesis that previous fluconazole use may promote de novo resistance through the CgPDR1-dependent3 upregulation of drug efflux pump-encoding genes CgCDR1 and CgCDR2 and also CgSNQ2.4 In fact, in our study,2 expression of these genes was upregulated in both the fluconazole-resistant and fluconazole-susceptible–dose-dependent isolates, but not in the fluconazole-susceptible isolates, making it likely that their reduced fluconazole susceptibility was acquired or induced following drug exposure. Our recent findings5 showed that CgPDR1 hyperactive alleles not only conferred a selective growth advantage compared with the wildtype allele in the murine model of systemic candidiasis in the absence of fluconazole, but also contributed to fluconazole treatment failure in the mouse model. Finally, in our study,2 we observed that 6 of 7 patients receiving inadequate initial antifungal treatment died, and 5 of these patients were infected by a fluconazole-resistant isolate and empirically treated with fluconazole, supporting the conclusion that reduced susceptibility of C glabrata to fluconazole contributes to a poor outcome after invasive infection, especially in conjunction with inadequate empirical antifungal treatment. When considering the larger population size studied by Lee et al,1 it would have been interesting if they had extended their analysis to this important issue. Correspondence: Dr Posteraro, Istituto di Microbiologia, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Roma, Italy (firstname.lastname@example.org). References 1. Lee IFishman NOZaoutis TE et al. Risk factors for fluconazole-resistant Candida glabrata bloodstream infections. Arch Intern Med 2009;169 (4) 379- 383PubMedGoogle ScholarCrossref 2. Tumbarello MSanguinetti MTrecarichi EM et al. Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: risk factors, antifungal treatment and outcome. J Antimicrob Chemother 2008;62 (6) 1379- 1385PubMedGoogle ScholarCrossref 3. Vermitsky JPEarhart KDSmith WLHomayouni REdlind TDRogers PD Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol 2006;61 (3) 704- 722PubMedGoogle ScholarCrossref 4. Torelli RPosteraro BFerrari S et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol 2008;68 (1) 186- 201PubMedGoogle ScholarCrossref 5. Ferrari SIscher FCalabrese D et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog 2009;5 (1) e1000268PubMedGoogle ScholarCrossref
Archives of Internal Medicine – American Medical Association
Published: Aug 10, 2009
Keywords: fluconazole,fungemia,candida glabrata
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